ABSTRACT. Soluble oligomers of beta amyloid (A?) protein are the most potent neuroactive structural form of this protein and evidence suggests they cause the synaptotoxic changes resulting in cognitive decline in Alzheimer?s disease (AD) (Selkoe and Hardy 2016, Viola and Klein 2015). A safe and effective drug against A? oligomers should prevent and reverse this synaptotoxicity. CT1812 is the first drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). This first-in-class drug works by displacing A? oligomers bound to neuronal receptors at synapses. It accomplish this by allosterically modulating a key protein regulator of oligomer receptors (the sigma- 2/PGRMC1 protein complex), thus destabilizing the oligomer binding site and increasing the off-rate of oligomers, which are then rapidly cleared into the CSF (within hours). As a result, CT1812 restores synapse number and cognitive performance to normal in preclinical AD mouse models (Izzo et al., 2014a, b). This project proposes to evaluate whether CT1812 can rapidly clear A? oligomers into the CSF in Alzheimer?s patients by conducting a Phase 1b randomized, double-blind, placebo-controlled clinical trial in 16 A?-positive mild to moderate Alzheimer?s patients (MMSE 18-26). Following indwelling catheter placement in the lumbar spinal cord by an experienced anesthesiologist and collection of hourly baseline CSF samples for 4 hours, a single oral dose of CT1812 or placebo is given, followed by hourly sampling of the CSF for 24 hours. Samples are subsequently analyzed for A? oligomer concentrations by oligomer-selective immunoassay. Our primary aim is to evaluate oligomer concentrations in the CSF in CT1812-treated vs. placebo-treated AD patients over 24 hours and correlate these levels with concentrations of CT1812 in the plasma and CSF. Our secondary aim is to evaluate changes in CSF protein markers associated with Alzheimer?s disease and synaptic damage (including neurogranin and SNAP25). By measuring oligomers displaced by CT1812 and cleared into CSF, this trial can directly test the mechanism of action of CT1812 and identify CSF oligomers as a biomarker of CT1812 target engagement in AD patients. We hypothesize that increases in CSF oligomer concentration following CT1812 treatment, but not placebo treatment, will be demonstrated in this trial, and that these changes will correlate with the overall plasma and CSF concentrations of CT1812. Completion of this pilot study in AD patients will inform the design and methods of the subsequent Phase 2a proof of concept trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 36 million people worldwide suffering from AD and MCI due to AD, for whom no disease-modifying pharmacological treatments exist.